1. Field of the Invention
The present invention relates to preparation of injectable compositions. More particularly, the present invention relates to injectable suspensions having improved injectability, and to methods for the preparation of such injectable suspensions.
2. Related Art
Injectable suspensions are heterogeneous systems that typically consist of a solid phase dispersed in a liquid phase, the liquid phase being aqueous or nonaqueous. To be effective and pharmaceutically acceptable, injectable suspensions should preferably be: sterile; stable; resuspendable; syringeable; injectable; isotonic; and nonirritating. The foregoing characteristics result in manufacturing, storage, and usage requirements that make injectable suspensions one of the most difficult dosage forms to develop.
Injectable suspensions are parenteral compositions in that they are introduced into an organism or host by means other than through the gastrointestinal tract. Particularly, injectable suspensions are introduced into a host by subcutaneous (SC) or intramuscular (IM) injection. Injectable suspensions may be formulated as a ready-to-use injection or require a reconstitution step prior to use. Injectable suspensions typically contain between 0.5% and 5.0% solids, with a particle size of less than 5 xcexcm for IM or SC administration. Parenteral suspensions are frequently administered through needles about one-half to two inches long, 19 to 22 gauge, with an internal diameter in the range of 700 to 400 microns, respectively.
To develop an effective and pharmaceutically acceptable injectable suspension, a number of characteristics must be evaluated. These characteristics include syringeability, injectability, clogging, resuspendability, and viscosity. As will be readily apparent to one skilled in the art, other characteristics and factors should be considered in developing an injectable suspension (see, for example, Floyd, A. G. and Jain, S., Injectable Emulsions and Suspensions, Chapter 7 in Pharmaceutical Dosage Forms: Disperse Systems Vol. 2, Edited by Lieberman, H. A., Rieger, M. M., and Banker, G. S., Marcel Dekker, New York (1996), the entirety of which is incorporated herein by reference and referred to herein as xe2x80x9cthe Floyd et al. Chapterxe2x80x9d).
Syringeability describes the ability of an injectable suspension to pass easily through a hypodermic needle on transfer from a vial prior to injection. It includes characteristics such as ease of withdrawal, clogging and foaming tendencies, and accuracy of dose measurements. As described in the Floyd et al. Chapter, increase in the viscosity, density, particle size, and concentration of solids in suspension hinders the syringeability of suspensions.
Injectability refers to the performance of the suspension during injection. Injectability includes factors such as pressure or force required for injection, evenness of flow, aspiration qualities, and freedom from clogging.
Clogging refers to the blockage of syringe needles while administering a suspension. It may occur because of a single large particle, or an aggregate that blocks the lumen of the needle due to a bridging effect of the particles. Clogging at or near the needle end may be caused by restrictions to flow from the suspension. This may involve a number of factors, such as the injection vehicle, wetting of particles, particle size and distribution, particle shape, viscosity, and flow characteristics of the suspension.
Resuspendability describes the ability of the suspension to uniformly disperse with minimal shaking after it has stood for some time. Resuspendability can be a problem for suspensions that undergo xe2x80x9ccakingxe2x80x9d upon standing due to settling of the deflocculated particles. xe2x80x9cCakingxe2x80x9d refers to a process by which the particles undergo growth and fusion to form a nondispersible mass of material.
Viscosity describes the resistance that a liquid system offers to flow when it is subjected to an applied shear stress. A more viscous system requires greater force or stress to make it flow at the same rate as a less viscous system. A liquid system will exhibit either Newtonian or non-Newtonian flow based on a linear or a non-linear increase, respectively, in the rate of shear with the shearing stress. Structured vehicles used in suspensions exhibit non-Newtonian flow and are typically plastic, pseudoplastic, or shear-thinning with some thixotropy (exhibiting a decrease in viscosity with an increase in the rate of shear).
In design of injection vehicles, viscosity enhancers are added in order to retard settling of the particles in the vial and syringe. However, viscosity is typically kept low, in order to facilitate mixing, resuspension of the particles with the vehicle, and to make the suspension easier to inject (i.e., low force on the syringe plunger). For example, Lupron Depot from TAP Pharmaceuticals (mean particle size of approximately 8 xcexcm) utilizes an injection vehicle with a viscosity of approximately 5.4 cp. The fluid phase of a suspension of Decapeptyl from DebioPharm (mean particle size of approximately 40 xcexcm), when prepared as directed, has a viscosity of approximately 19.7 cp. Conventional parenteral suspensions are dilute, with limitations for viscosity because of syringeability and injectability constraints. See, for example, the Floyd, et al. Chapter noted above.
Injectable compositions containing microparticle preparations are particularly susceptible to injectability problems. Microparticle suspensions may contain 10-15% solids, as compared with 0.5-5% solids in other types of injectable suspensions. Microparticles, particularly controlled release microparticles containing an active agent or other type of substance to be released, range in size up to about 250 xcexcm, as compared with a particle size of less than 5 xcexcm recommended for IM or SC administration. The higher concentration of solids, as well as the larger solid particle size, make it more difficult to successfully inject microparticle suspensions. This is particularly true since it is also desired to inject the microparticle suspensions using as small a needle as possible to minimize patient discomfort.
Thus, there is a need in the art for an injectable composition with improved injectability. There is a particular need in the art for an injectable composition that solves the injectability problems associated with microparticle suspensions. The present invention, the description of which is fully set forth below, solves the need in the art for such injectable compositions.
The present invention relates to injectable compositions having improved injectability, and to methods for the preparation of such injectable compositions. In one aspect of the invention, a composition suitable for injection through a needle into a host is provided. The composition comprises microparticles having a polymeric binder, with a mass median diameter of at least about 10 xcexcm. The composition also includes an aqueous injection vehicle (the injection vehicle not being the aqueous injection vehicle that consists of 3% by volume sodium carboxymethyl cellulose, 1% by volume polysorbate 20, 0.9% by volume sodium chloride, and a remaining percentage by volume of water). The microparticles are suspended in the injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, the fluid phase of the suspension having a viscosity of at least 20 cp at 20xc2x0 C. In other embodiments, the fluid phase of the suspension has a viscosity at 20xc2x0 C. of at least about 30 cp, 40 cp, 50 cp, and 60 cp. The composition may also comprise a viscosity enhancing agent, a density enhancing agent, a tonicity enhancing agent, and/or a wetting agent. The composition can be administered to a host by injection.
In another aspect of the present invention, a method of making a composition suitable for injection through a needle into a host is provided. The method comprises:
(a) providing microparticles comprising a polymeric binder, said microparticles having a mass median diameter of at least about 10 xcexcm;
(b) providing an aqueous injection vehicle having a viscosity of at least 20 cp at 20xc2x0 C., wherein said injection vehicle is not the aqueous vehicle consisting of 3% by volume sodium carboxymethyl cellulose, 1% by volume polysorbate 20, 0.9% by volume sodium chloride, and a remaining percentage by volume of water; and
(c) suspending the microparticles in the aqueous injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension.
In a further aspect of the present invention, another method for preparing a composition suitable for injection through a needle into a host is provided. In such a method, dry microparticles are mixed with an aqueous injection vehicle to form a first suspension. The first suspension is mixed with a viscosity enhancing agent to form a second suspension. The viscosity enhancing agent increases the viscosity of the fluid phase of the second suspension. The first suspension may be withdrawn into a first syringe, prior to mixing with the viscosity enhancing agent. The first suspension may be mixed with the viscosity enhancing agent by coupling the first syringe containing the first suspension to a second syringe that contains the viscosity enhancing agent. The first suspension and the viscosity enhancing agent are then repeatedly passed between the first and second syringes.
In yet a further aspect of the present invention, a method for administering a composition to a host is provided. The method comprises:
(a) mixing dry microparticles with an aqueous injection vehicle to form a first suspension;
(b) mixing the first suspension with a viscosity enhancing agent to form a second suspension, wherein the viscosity enhancing agent increases the viscosity of the fluid phase of the second suspension; and
(c) injecting the second suspension into the host.
In still a further aspect of the present invention, another method for administering a composition to a host is provided. The method comprises:
(a) mixing dry microparticles with an aqueous injection vehicle to form a suspension, wherein the aqueous injection vehicle has a viscosity at 20xc2x0 C. of less than about 60 cp;
(b) changing the viscosity of the fluid phase of the suspension;
(c) withdrawing the suspension into a syringe; and
(d) injecting the suspension from the syringe into the host.
In a further aspect of the invention, step (b) is carried out by changing the temperature of the fluid phase of the suspension. In another aspect, step (c) is performed prior to step (b). Step (b) may be carried out by adding a viscosity enhancing agent to the suspension in the syringe to thereby increase the viscosity of the fluid phase of the suspension.
In still a further aspect of the invention, a method for preparing a composition suitable for injection through a needle into a host is provided. The method comprises:
(a) mixing dry microparticles with an aqueous injection vehicle that comprises a viscosity enhancing agent to form a suspension;
(b) removing water from the suspension; and
(c) reconstituting the suspension with a quantity of sterile water for injection to form an injectable suspension, wherein the quantity of sterile water for injection is sufficient to achieve a viscosity of a fluid phase of the injectable suspension that provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
Features and Advantages
A feature of the present invention is that the injectable compositions can be used to inject varying types of microparticles, and varying types of active agents or other substances, into a host.
A further feature of the present invention is that it allows microparticles to be wetted to achieve a homogeneous suspension, while improving injectability into a host and reducing in vivo injectability failures.
The present invention advantageously provides medically acceptable injectability rates for high concentration suspensions, and for suspensions having large particle size.
The present invention also advantageously provides an efficient method of improving in vivo injectability without introducing microbial contamination or compromising aseptic conditions.
Overview
The present invention relates to injectable compositions having improved injectability, and to methods for the preparation of such injectable compositions. The injectable compositions of the present invention overcome injectability problems, particularly injectability failures that occur upon injection into muscle or subcutaneous tissue. Such injectability failures will be referred to herein as xe2x80x9cin vivo injectability failures.xe2x80x9d In vivo injectability failures often manifest themselves in the form of a plug at the tip of the needle, and occur immediately or shortly after injection has been initiated. In vivo injectability failures are typically not predicted by laboratory or other in vitro testing.
The inventors have unexpectedly discovered that injectability is improved, and in vivo injectability failures significantly and unexpectedly reduced, by increasing the viscosity of the fluid phase of an injectable suspension. This is in contrast to conventional teachings that an increase in the viscosity hinders injectability and syringeability.
Viscous vehicles, however, are not optimal for preparing homogeneous suspensions of microparticles because of the relative inability of viscous vehicles to penetrate and wet out a mass of dry particles. Suspensions prepared with viscous vehicles are prone to clump irreversibly. Consequently, such suspensions are not injectable via needles of medically acceptable size. A further disadvantage of viscous suspensions is the lack of ease of transferring such suspensions from the vial or container used to prepare the suspension to the syringe used for injection.
The present invention also solves the additional problems that arise from use of a viscous injection vehicle. In accordance with the present invention, microparticles are suspended in an injection vehicle having suitable wetting characteristics. The viscosity of the fluid phase of the injectable suspension is increased prior to injecting the suspension in order to improve injectability, and to reduce in vivo injectability failures.
To ensure clarity of the description that follows, the following definitions are provided. By xe2x80x9cmicroparticlesxe2x80x9d or xe2x80x9cmicrospheresxe2x80x9d is meant particles that contain an active agent or other substance dispersed or dissolved within a polymer that serves as a matrix or binder of the particle. The polymer is preferably biodegradable and biocompatible. By xe2x80x9cbiodegradablexe2x80x9d is meant a material that should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body. The products of the biodegradation should also be biocompatible with the body. By xe2x80x9cbiocompatiblexe2x80x9d is meant not toxic to the body, is pharmaceutically acceptable, is not carcinogenic, and does not significantly induce inflammation in body tissues. As used herein, xe2x80x9cbodyxe2x80x9d preferably refers to the human body, but it should be understood that body can also refer to a non-human animal body. By xe2x80x9cweight %xe2x80x9d or xe2x80x9c% by weightxe2x80x9d is meant parts by weight per hundred parts total weight of microparticle. For example, 10 wt. % active agent would mean 10 parts active agent by weight and 90 parts polymer by weight. Unless otherwise indicated to the contrary, percentages (%) reported herein are by volume. By xe2x80x9ccontrolled release microparticlexe2x80x9d or xe2x80x9csustained release microparticlexe2x80x9d is meant a microparticle from which an active agent or other type of substance is released as a function of time. By xe2x80x9cmass median diameterxe2x80x9d is meant the diameter at which half of the distribution (volume percent) has a larger diameter and half has a smaller diameter.